dc.contributor.author
Tan, Zhijia
dc.contributor.author
Niu, Ben
dc.contributor.author
Tsang, Kwok Yeung
dc.contributor.author
Melhado, Ian G.
dc.contributor.author
Ohba, Shinsuke
dc.contributor.author
He, Xinjun
dc.contributor.author
Huang, Yongheng
dc.contributor.author
Wang, Cheng
dc.contributor.author
McMahon, Andrew P.
dc.contributor.author
Jauch, Ralf
dc.contributor.author
Chan, Danny
dc.contributor.author
Zhang, Michael Q.
dc.contributor.author
Cheah, Kathryn S. E.
dc.date.accessioned
2018-08-01T08:23:50Z
dc.date.available
2018-08-01T08:23:50Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/22595
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-401
dc.description.abstract
The growth plate mediates bone growth where SOX9 and GLI factors control chondrocyte proliferation, differentiation and entry into hypertrophy. FOXA factors regulate hypertrophic chondrocyte maturation. How these factors integrate into a Gene Regulatory Network (GRN) controlling these differentiation transitions is incompletely understood. We adopted a genome-wide whole tissue approach to establish a Growth Plate Differential Gene Expression Library (GP-DGEL) for fractionated proliferating, pre-hypertrophic, early and late hypertrophic chondrocytes, as an overarching resource for discovery of pathways and disease candidates. De novo motif discovery revealed the enrichment of SOX9 and GLI binding sites in the genes preferentially expressed in proliferating and prehypertrophic chondrocytes, suggesting the potential cooperation between SOX9 and GLI proteins. We integrated the analyses of the transcriptome, SOX9, GLI1 and GLI3 ChIP-seq datasets, with functional validation by transactivation assays and mouse mutants. We identified new SOX9 targets and showed SOX9-GLI directly and cooperatively regulate many genes such as Trps1, Sox9, Sox5, Sox6, Col2a1, Ptch1, Gli1 and Gli2. Further, FOXA2 competes with SOX9 for the transactivation of target genes. The data support a model of SOX9-GLI-FOXA phasic GRN in chondrocyte development. Together, SOX9-GLI auto-regulate and cooperate to activate and repress genes in proliferating chondrocytes. Upon hypertrophy, FOXA competes with SOX9, and control toward terminal differentiation passes to FOXA, RUNX, AP1 and MEF2 factors.
en
dc.format.extent
32 Seiten
de
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
de
dc.subject
SOX9-GLI-FOXA phasic transcriptional network
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::572 Biochemie
de
dc.title
Synergistic co-regulation and competition by a SOX9-GLI-FOXA phasic transcriptional network coordinate chondrocyte differentiation transitions
de
dc.type
Wissenschaftlicher Artikel
de
dcterms.bibliographicCitation.articlenumber
e1007346
dcterms.bibliographicCitation.doi
10.1371/journal.pgen.1007346
dcterms.bibliographicCitation.journaltitle
PLoS Genetics
dcterms.bibliographicCitation.number
4
dcterms.bibliographicCitation.volume
14
dcterms.bibliographicCitation.url
https://doi.org/10.1371/journal.pgen.1007346
de
refubium.affiliation
Biologie, Chemie, Pharmazie
de
refubium.affiliation.other
Institut für Chemie und Biochemie

de
refubium.note.author
Der Artikel wurde in einer reinen Open-Access-Zeitschrift publiziert.
de
refubium.resourceType.isindependentpub
no
de
dcterms.accessRights.openaire
open access
dcterms.isPartOf.issn
1553-7404